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Human mutations in SLITRK3 implicated in GABAergic synapse development in mice

Authors :
Stephanie Efthymiou
Wenyan Han
Muhammad Ilyas
Jun Li
Yichao Yu
Marcello Scala
Nancy T. Malintan
Nikoleta Vavouraki
Kshitij Mankad
Reza Maroofian
Clarissa Rocca
Vincenzo Salpietro
Shenela Lakhani
Eric J. Mallack
Timothy Blake Palculict
Hong Li
Guojun Zhang
Faisal Zafar
Nuzhat Rana
Noriko Takashima
Hayato Matsunaga
Claudia Manzoni
Pasquale Striano
Mark F. Lythgoe
Jun Aruga
Wei Lu
Henry Houlden
Source :
Frontiers in Molecular Neuroscience, Vol 17 (2024)
Publication Year :
2024
Publisher :
Frontiers Media S.A., 2024.

Abstract

This study reports on biallelic homozygous and monoallelic de novo variants in SLITRK3 in three unrelated families presenting with epileptic encephalopathy associated with a broad neurological involvement characterized by microcephaly, intellectual disability, seizures, and global developmental delay. SLITRK3 encodes for a transmembrane protein that is involved in controlling neurite outgrowth and inhibitory synapse development and that has an important role in brain function and neurological diseases. Using primary cultures of hippocampal neurons carrying patients’ SLITRK3 variants and in combination with electrophysiology, we demonstrate that recessive variants are loss-of-function alleles. Immunostaining experiments in HEK-293 cells showed that human variants C566R and E606X change SLITRK3 protein expression patterns on the cell surface, resulting in highly accumulating defective proteins in the Golgi apparatus. By analyzing the development and phenotype of SLITRK3 KO (SLITRK3–/–) mice, the study shows evidence of enhanced susceptibility to pentylenetetrazole-induced seizure with the appearance of spontaneous epileptiform EEG as well as developmental deficits such as higher motor activities and reduced parvalbumin interneurons. Taken together, the results exhibit impaired development of the peripheral and central nervous system and support a conserved role of this transmembrane protein in neurological function. The study delineates an emerging spectrum of human core synaptopathies caused by variants in genes that encode SLITRK proteins and essential regulatory components of the synaptic machinery. The hallmark of these disorders is impaired postsynaptic neurotransmission at nerve terminals; an impaired neurotransmission resulting in a wide array of (often overlapping) clinical features, including neurodevelopmental impairment, weakness, seizures, and abnormal movements. The genetic synaptopathy caused by SLITRK3 mutations highlights the key roles of this gene in human brain development and function.

Details

Language :
English
ISSN :
16625099
Volume :
17
Database :
Directory of Open Access Journals
Journal :
Frontiers in Molecular Neuroscience
Publication Type :
Academic Journal
Accession number :
edsdoj.4c9fba0e92c64e6881b4e82760b9b3c3
Document Type :
article
Full Text :
https://doi.org/10.3389/fnmol.2024.1222935